Previous studies by ourselves and others have demonstrated that immunoregulatory-suppressor lymphocytes are both a component of the normal immune system and are associated with the pathogenesis of several primary and secondary immunodeficiency diseases. Recent evidence suggests that suppressor cells function through the release of soluble immunoregulatory factors. Natural killer (NK) cells and cells mediating antibody-dependent cellular cytotoxicity (ADCC) are also being examined for immunoregulatory activities in addition to their suggested role in immune surveillance against tumors. These investigations will extend our ongoing analysis of the cellular and biochemical mechanisms underlying suppressor-cell activity and examine the complex interactions regulating NK and ADCC functions. Preliminary studies indicate that these cytotoxic activities may be self-regulated through an autologous mixed lymphocyte reaction. Emphasis will be placed on the biochemical isolation and characterization of soluble suppressor factor(s) (SSF) derived from cultured human lymphocytes and shown to inhibit a wide spectrum of humoral and cell-mediated immune functions, including NK and ADCC activities. We have observed that low levels of similar soluble suppressor activity can also be found in sera from healthy donors and in significantly increased levels in sera from patients with malignant disease. Serum SSF activity will thus be correlated with extent of disease and any associated deficiencies of immunologic function. Culture-derived and serum-derived SSF will be purified using differential ultrafiltration, molecular sieve and ion exchange chromatography, and high-pressure liquid chromatography. Homogeneous preparations will be biochemically characterized and culture-derived SSF will be compared to active fractions isolated from sera of patients and normal donors. We shall also prepare heterologous and monoclonal antibodies against SSF for use in quantitative immunoassays. Exogenous modulation of immunoregulatory activity may have subsequent therapeutic potential. Thus we further intend to examine the ability of irradiation, immunopharmacologically active compounds and biological modifier substances to stimulate or decrease suppressor-cell activity in vitro with the eventual goal of therapeutic application to immunodeficiency states and autoimmune disorders. Clinical studies will examine serum-\and culture-derived SSF in aging and immunodeficiency diseases. Murine and human SSF will be used in vivo to treat the disorder of NZB/W F1 mice associated with suppressor-cell deficiency. (IS)